Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance

Abstract

Substituted heterocyclic compounds for treating multidrug resistance are disclosed. Compositions and methods of use for the substituted heterocyclic compounds are disclosed. Suitable substituted heterocyclic compounds include:

What is claimed is:  
     
       1. A compound having a formula:                    
       or an optical isomer, diastereomer, enantiomer, or pharmaceutically-acceptable salt thereof, wherein: 
       (a) A is A 1 ;  
       (b) A 1  is a group having a formula:                    
       wherein: 
       (i) each R 1  is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;  
       (ii) x is 1 to 10;  
       (iii) R 2  is selected from the group consisting of a substituted hydrocarbon group and a substituted heterogeneous group;  
       (iv) D 1  and D 2  are each independently selected from the group consisting of —C(O)— and —NR 3 —, wherein R 3  is selected from the group consisting of a hydrogen atom, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocycle group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; wherein, optionally, R 2  and R 3  may be bonded together to form a ring selected from the group consisting of a heterocyclic group and a substituted heterocyclic group;  
       (v) y is 0 or 1 and z is 0 or 1;  
       with the provisos that when y is 0, z is 1 and when y is 1, z is 0, when y is 0 and D 1  is —NR 3 —, then D 2  is —C(O)—, when y is 0 and D 2  is —NR 3 —, then D 1  is —C(O)—; and 
       (c) A 2  is a group having a formula:                    
       wherein: 
       (i) each R 1  is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;  
       (ii) u is 0 to 10;  
       (iii) p is 0 to about 10;  
       (iv) v is 0 or 1;  
       (v) D 3  is selected from the group consisting of —S(O) 2 —, —C(O)—, and CR 1 (OH)—, with the provisos that when D 3  is —S(O) 2 —, then D 1  is —C(O)—, D 2  is —NR 3 —, and R 2  and R 3  are bonded together to form the ring structure, and when D 3  is —C(O)—, v is 0, and R 5  contains a —C(O)— group, then p is not 0; and  
       (vi) R 5  is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; wherein when A is A 1  then R 1  is a heteroaromatic group.  
     
     
       2. The compound of  claim 1 , wherein u is 1 to 3, p is 1 to 3, and v is 1. 
     
     
       3. The compound of  claim 2 , wherein D 3  is —CR 1 (OH)—. 
     
     
       4. The compound of  claim 3 , wherein R 5  is a heteroaromatic group of the formula:                    
       wherein each X is independently selected from the group consisting of CH and a heteroatom, with the proviso that at least one X is a heteroatom. 
     
     
       5. The compound of  claim 4 , wherein A is A 1 , R 2  and R 3  are bonded together and the ring structure has 4 to 6 members in the ring. 
     
     
       6. The compound of  claim 5 , wherein the compound has a formula selected from the group consisting of:                  
                   
     
     
       7. The compound of  claim 4 , wherein A is A 1 , D 1  is —C(O)—, and D 2  is —NR 3 —. 
     
     
       8. The compound of  claim 7 , wherein the compound has a formula selected from the group consisting of:                  
                   
     
     
       9. The compound of  claim 1 , wherein D 1  is —C(O)—, y is 1, and z is 0. 
     
     
       10. The compound of  claim 1 , wherein D 1  is —NR 3 — and D 2  is —C(O)—. 
     
     
       11. The compound of  claim 10 , wherein R 3  is selected from the group consisting of hydrogen and a hydrocarbon group. 
     
     
       12. The compound of  claim 1 , wherein u is 0, and R 5  is selected from the group consisting of an aromatic group; a substituted aromatic group; a heteroaromatic group; a substituted heteroaromatic group; a hydrocarbon group; a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and a substituted heterogeneous group, wherein the substituted heterogeneous group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group. 
     
     
       13. The compound of  claim 12 , wherein p is 0, and D 3  is —SO 2 —. 
     
     
       14. The compound of  claim 1 , wherein D 4  is —C(O)—, t is 0, and D 5  is —C(O)R 6 . 
     
     
       15. The compound of  claim 1 , wherein D 4  is —C(O)— and D 5  is —O r R 6 . 
     
     
       16. The compound of  claim 1 , wherein it is —CH(R 1 )— and D 5  is —O r R 6 . 
     
     
       17. The compound of  claim 1 , wherein it is —CH(R 1 )— and D 5  is —NR 6 (R 7 )—. 
     
     
       18. The compound of  claim 1 , wherein D 4  is —C(O)— and D 5  is —NR 6 (R 7 ). 
     
     
       19. A composition comprising: 
       (a) the compound according to  claim 1 ; and  
       (b) a pharmaceutically acceptable carrier.  
     
     
       20. The composition according to  claim 19 , wherein the compound inhibits transport protein activity. 
     
     
       21. A composition comprising: 
       (a) the compound according to  claim 8 ; and  
       (b) a pharmaceutically acceptable carrier.  
     
     
       22. The composition according to  claim 21 , wherein the compound inhibits transport protein activity. 
     
     
       23. A method of treating multidrug resistance comprising administering to a mammal in need of such treatment or inhibition the composition according to  claim 19 . 
     
     
       24. A method of treating multidrug resistance, comprising administering to a mammal in need of such treatment or inhibition the composition according to  claim 21 .